1. Field of the Invention
The present invention relates to the use of inhibitors of nitric oxide synthase (NOS) for the attenuation of the opioid withdrawal syndrome. It is applicable to human drug addicts who are dependent on drugs like heroin, or who have been maintained for a period of time on methadone, and wish to be completely free of drugs.
2. Description of Related Art
Two major classes of drugs are presently used to attenuate the opioid withdrawal syndrome. The first class includes .varies..sub.2 -adrenoceptor agonists, of which clonidine is the most commonly used (J. H. Jaffe, "Drug addiction and drug abuse," The Pharmacological Basis of Therapeutics, A. G. Gilman et al., eds., Pergamon Press, New York, 1991, pp. 522-573). .varies..sub.2 -Adrenoceptor agonists presumably act on the same neurons, but at a different receptor, as those affected by opioids (Aghajanian, G. K., "The neurobiology of opiate withdrawal: receptors, second messengers, and ion channels," Psychiatry Letter III:57-60, 1985). Clonidine is an effective attenuator of the opioid withdrawal syndrome. The major problem with its use, however, is that it lowers blood pressure. Therefore, its effectiveness is limited by the susceptibility of the patient to this effect. Another drug currently being tested for the treatment of opioid withdrawal is the mixed agonist-antagonist opioid buprenorphine (Mello et al., "Buprenorphine effects on human heroin self-administration." J. Pharmacol. Exp. Ther., 223:30-39, 1982). Presumably, mixed agonist-antagonists work to attenuate the withdrawal syndrome at the opioid receptor itself. This drug is also effective, but suffers from potential abuse liability because of its opioid agonist properties (Fudala et al., "Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal," Clin. Pharmacol. and Ther., 47:525-534, 1990).
Data from animal experiments have linked opioid withdrawal and activation of glutamatergic neurotransmission (Rasmussen et al., "Withdrawal-induced activation of locus coeruleus neurons in opiate-dependent rats: attenuation by lesions of the nucleus paragigantocellularis," Brain Research 505:346-350, 1989; Rasmussen et al., "NMDA antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal," Eur. J. Pharmacol. 197:9-16, 1991). Recently, Trujillo et al. ("Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801," Science 251:85-87, 1991) reported that inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptor with MK-801 effectively attenuates jumping behavior observed in opioid-dependent rats during withdrawal, suggesting a new intervention strategy, i.e., inhibition of the NMDA neurotransmission. The class of drugs to which MK-801 belongs blocks the NMDA-gated ionic channel. Drugs of this class, which includes phencyclidine, have abuse liability, and produce untoward side effects such as hallucinations and bizarre behavior. Moreover, they produce neurotoxicity, which limits their use as pharmaceuticals (Olney et al., "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs," Science 244:1360-1362, 1989).